| Abstrakt: |
The overall aim of these studies was to investigate the oral and i.m. bioavailability of CDB-2914 in intact female rhesus monkeys, and to compare the serum concentrations of CDB-2914 with that of mifepristone following oral administration. In the first study, a 50 mg bolus of CDB-2914 per monkey was administered intravenously, orally or intramuscularly. The area under the serum concentration–time curve for 72 h (AUC0–72) following i.v. injection was 18 320 ± 2718 ng/ml•h, and that for oral administration was 10 464 ± 3248 ng/ml•h. Thus, the oral bioavailability of CDB-2914 equivalents was 56%. The AUC0–168 h following i.m. injection was 11 226 ± 1130 ng/ml•h. Therefore, the i.m. bioavailability of CDB-2914 equivalents was 62%. In the second study, the serum concentrations of CDB-2914 and mifepristone equivalents were compared following an oral bolus dose in two different formulations. When administered at 5 mg/kg in aqueous suspending vehicle (ASV), the mean peak serum concentration (Cmax) of CDB-2914 equivalents (192 ± 64 ng/ml) occurred at 5 ± 1 h, whereas the Cmax of mifepristone equivalents (82 ± 25 ng/ml) occurred at 3 ± 1 h. Following administration in gelatin capsules (35 mg/monkey), the Cmax of CDB-2914 equivalents (129 ± 24 ng/ml) occurred at 5 ± 1 h, while the Cmax of mifepristone equivalents (31 ± 8 ng/ml) occurred at 3 ± 1 h. The serum concentration (AUC0–120 h) of CDB-2914 equivalents was 4.7- or 5.3-fold greater than that of mifepristone equivalents when administered orally in ASV or gelatin capsules respectively. The serum protein binding characteristics of CDB-2914 were also studied. CDB-2914 bound to human α1-acid glycoprotein (AAG), but not with as high an affinity as mifepristone. In contrast, neither CDB-2914 nor mifepristone bound with high affinity to AAG, corticosteroid binding globulin or sex hormone binding globulin in monkey serum. Collectively, these results indicated that CDB-2914 was more efficiently absorbed than mifepristone following oral administration to female rhesus monkeys. |
